Alzheimer's disease (AD) is a neurodegenerative disease for which there is at present no cure. AD causes dementia in about 10% of the population above the age of 65 (Geldmacher and Whitehouse, N. Eng. J. Med. 335:330, 1996). Due to the widespread nature of the disease in the population of aging persons, much research has been conducted to determine the underlying cause or causes of AD so that treatments can be developed. There are several theories as to the processes underlying AD, including abnormal protein tau (Goedert et al., Nature 383:550 (1996); Lee, Curr. Opin. Neurobiol. 5:663 (1995)), aberrant processing of the .beta.-amyloid precursor protein (Selkoe, Neuron 6:487 (1991); Multhaup et al., Biol. Chem. Hoppe-Seyler 374:1 (1993); Gandy and Greengard, Int. Rev. Neurobiol. 36:29 (1994)) and expression of apolipoprotein E (Roses, Annu. Rev. Med. 47:387 (1996)). Even with the significant amount of research into AD, no cause has yet been identified. Consequently, no definitively efficacious treatments have been developed for alleviating the effects of the neurodegeneration of AD. Nevertheless, several studies have demonstrated that persons treated with compounds such as nonsteroidal antiinflammatory drugs NSAIDs), estrogen, vitamin E, or nicotine have lower rates of AD than the general population
The only certain diagnosis of AD to date is via post-mortem analysis of an individual's brain. The brain tissue of persons afflicted with AD exhibits a characteristic accumulation of neurofibrillary tangles which include the processed .beta.-amyloid protein. While post-mortem diagnosis is unequivocal, it clearly does not inform a patient's physician within a time that the physician could attempt therapeutic measures.
While it is thought that the pathophysiology of AD arises in the central nervous system (CNS), there are non-CNS manifestations of AD, including changes in the blood and the skin (Scott, J. Am. Geriatr. Soc. 41:268 (1993); Joachim et al., Nature 341:226 (1989)). Advantageously, these non-CNS manifestations of AD involve physiological processes which can be tested in tissues accessible by non-invasive or minimally invasive procedures. Some progress has been made toward the diagnosis of AD in living patients by measuring the differences between physiological processes of normal individuals and those of AD patients. Unfortunately, diagnostic procedures based on such differences are presently not reliable predictors of progression to AD.
One example of such a non-CNS physiological process which may be useful for diagnosing AD is the transport of anions by the erythrocyte (red blood cell) membrane transporter band 3. Bosman et al. (Neurobiol Aging 12:13-18, 1991) postulated that AD might be the result of accelerated cellular aging of the neurons affected in AD. These investigators examined the parameters which were known to reflect the aging of the erythrocyte, including increased quantities of erythrocyte-bound immunoglobulin G (IgG) and altered anion transport by band 3. The latter parameter was determined by sulfate ion transport and analyzed using standard Michaelis-Menten kinetics.
The foregoing methods of analysis are inadequate for reliable diagnosis of AD in living persons. Thus, there is a need for methods of diagnosis of AD which are reliable, accurate, sensitive, non-invasive or minimally invasive, and which can be performed quickly and inexpensively using existing laboratory equipment. Further, there is a need for methods which can track the progression of AD. Accurate diagnostic methods will be of use in providing patients and physicians with information needed for responding to the personal and medical effects of AD.